This application for a Mentored Research Scientist Development Award (K01) describes a training program and research project that provides the candidate with the necessary skills and laboratory-based techniques to conduct clinical research studies and to make the transition to an independent researcher. Candidate: The candidate's long term goal is to develop his own research program focusing on the structural and functional alterations in human skeletal muscle that result from aging, disuse and disease. The candidate is a Research Associate at the University of Vermont with a background in engineering. He has, for the first time, applied the novel technique of sinusoidal analysis to single human skeletal muscle fibers;thereby allowing the first examinations of the molecular determinants of contractile function in humans. Environment: The University of Vermont is ideally suited to the candidate's proposed research and training. It includes a cohesive group of clinicians and basic science researchers engaged in clinical research and muscle physiology that examines function at the whole body, whole muscle, single fiber and single molecule levels. Research: The objective of the proposed research study is to characterize the molecular mechanisms underlying age-related changes in single human skeletal muscle fiber function. We hypothesize that aging impairs single fiber function by: 1) altering myosin kinetics (increasing myosin attachment time and decreasing myosin rate of force production) and 2) decreasing myosin heavy chain content. To test these hypotheses, contractile performance and myofibrillar protein expression from single skeletal muscle fibers will be obtained from young (21-35 yrs old) and elderly (65-75 yrs old) volunteers. The proposed studies will represent the first comprehensive examination of the mechanisms underlying human skeletal muscle contractile dysfunction with aging at the molecular level. Relevance: Understanding age-related skeletal muscle contractile dysfunction at the level of the myosin- actin cross-bridge is a necessary step towards developing more effective pharmacological and lifestyle countermeasures to correct sarcopenia that are directed specifically at molecular defects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AG031303-04
Application #
8129609
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Dutta, Chhanda
Project Start
2008-09-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2011
Total Cost
$126,332
Indirect Cost
Name
University of Vermont & St Agric College
Department
Physiology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Straight, Chad R; Ades, Philip A; Toth, Michael J et al. (2017) Age-related reduction in single muscle fiber calcium sensitivity is associated with decreased muscle power in men and women. Exp Gerontol 102:84-92
Toth, Michael J; Callahan, Damien M; Miller, Mark S et al. (2016) Skeletal muscle fiber size and fiber type distribution in human cancer: Effects of weight loss and relationship to physical function. Clin Nutr 35:1359-1365
Callahan, Damien M; Tourville, Timothy W; Miller, Mark S et al. (2015) Chronic disuse and skeletal muscle structure in older adults: sex-specific differences and relationships to contractile function. Am J Physiol Cell Physiol 308:C932-43
Miller, Mark S; Bedrin, Nicholas G; Ades, Philip A et al. (2015) Molecular determinants of force production in human skeletal muscle fibers: effects of myosin isoform expression and cross-sectional area. Am J Physiol Cell Physiol 308:C473-84
Callahan, Damien M; Bedrin, Nicholas G; Subramanian, Meenakumari et al. (2014) Age-related structural alterations in human skeletal muscle fibers and mitochondria are sex specific: relationship to single-fiber function. J Appl Physiol (1985) 116:1582-92
Miller, Mark S; Callahan, Damien M; Toth, Michael J (2014) Skeletal muscle myofilament adaptations to aging, disease, and disuse and their effects on whole muscle performance in older adult humans. Front Physiol 5:369
Callahan, Damien M; Miller, Mark S; Sweeny, Andrew P et al. (2014) Muscle disuse alters skeletal muscle contractile function at the molecular and cellular levels in older adult humans in a sex-specific manner. J Physiol 592:4555-73
Tanner, Bertrand C W; McNabb, Mark; Palmer, Bradley M et al. (2014) Random myosin loss along thick-filaments increases myosin attachment time and the proportion of bound myosin heads to mitigate force decline in skeletal muscle. Arch Biochem Biophys 552-553:117-27
Toth, Michael J; Miller, Mark S; Callahan, Damien M et al. (2013) Molecular mechanisms underlying skeletal muscle weakness in human cancer: reduced myosin-actin cross-bridge formation and kinetics. J Appl Physiol (1985) 114:858-68
Miller, Mark S; Toth, Michael J (2013) Myofilament protein alterations promote physical disability in aging and disease. Exerc Sport Sci Rev 41:93-9

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